Abstract Over 35 million patients are hospitalized each year in the U.S. with the expectation of safe medical care. Nevertheless, healthcare-associated infections are a leading cause of preventable morbidity and mortality. Risk of healthcare associated infections is highest in intensive care units (ICUs) where patients are vulnerable due to their critical health status and dependence on invasive medical devices for treatment and monitoring. We recently conducted the REDUCE MRSA Trial, a cluster-randomized trial of 74 ICUs that assessed the impact of daily chlorhexidine bathing and nasal mupirocin ointment for all ICU patients on healthcare-associated infections. We demonstrated a 37% reduction in MRSA clinical cultures as well as a 44% reduction in bloodstream infections using this universal decolonization approach. The proposed project will assess the degree to which the infection reduction associated with universal decolonization is mediated by reducing the number and size of outbreaks. We will quantify the reduction of MRSA clinical cultures and all-pathogen bloodstream infections attributable to outbreak prevention and reduction. Evidence of a significant impact on outbreak risk would demonstrate that decolonization decreases transmission of infectious agents in ICUs and would support the use of universal decolonization for outbreak prevention. If study results show no significant impact on outbreak risk, they would suggest that decolonization predominantly works through prevention of endogenous infection rather than prevention of transmission.